Why was colistin 'rediscovered' after 30 years out of favour?

The rise of multidrug-resistant gram-negative bacteria (especially *Pseudomonas aeruginosa* and *Acinetobacter baumannii*) in hospitals left clinicians with few options. Although colistin carries documented toxicity risks, it became the only remaining effective option for some serious infections. Regulators reassessed the risk-benefit balance and approved it as a last-line antibiotic.

What is the difference between colistin and colistimethate sodium?

Colistimethate sodium is a more water-soluble inactive prodrug form of colistin designed for intravenous administration. It is converted to colistin *in vivo*. Both the FDA and EMA approved colistimethate sodium for clinical use because it improves stability and reduces some toxicity issues compared to native colistin.

Is colistin still used today, or has it been replaced?

Colistin remains in active clinical use as a last-line agent for multidrug-resistant gram-negative infections, particularly in critically ill patients. It has not been replaced because resistance to colistin develops slowly, and few newer alternatives with activity against pan-resistant pathogens exist. It remains FDA-approved, EMA-authorised, and widely prescribed globally.

What are the main safety concerns with colistin?

[FDA and EMA labels highlight nephrotoxicity and neurotoxicity](https://www.fda.gov/drugs) as the primary adverse effects. Renal impairment is dose-related and sometimes reversible; neurotoxicity (paraesthesias, dizziness) can be more unpredictable. Close monitoring of renal function and neurological status is mandatory during therapy.

Why is inhaled colistin still under investigation if intravenous colistin is approved?

Inhaled formulations deliver colistin directly to the lungs at high concentrations while minimising systemic toxicity, making them ideal for respiratory infections like ventilator-associated pneumonia and cystic fibrosis lung disease. This targeted approach may improve efficacy and safety compared to intravenous dosing, which is why clinical research continues.

Colistin Regulatory History & Timeline

Colistin is an antibiotic peptide with a unique regulatory journey spanning over 70 years. Discovered in 1947 from Bacillus colistinus, it remained largely sidelined for decades due to toxicity concerns—until the rise of multidrug-resistant bacteria forced a regulatory and clinical reassessment. Today, colistin is FDA-approved, EMA-authorised, and Health Canada-approved as a last-line treatment for serious gram-negative infections. Its path to modern use mirrors the evolving landscape of antibiotic resistance and how regulators balance safety with unmet medical need.

Discovery & Early Development (1947–1970s)

Colistin was first isolated in 1947 from soil samples containing Bacillus colistinus, a gram-positive bacterium found in Japanese soil. Early microbiologists recognized its potent activity against gram-negative bacteria, making it chemically and biologically distinct from other antibiotics available at the time.

The compound exists in two main forms: colistin A and colistin B, both cyclic peptides. This polypeptide structure—rare among antibiotics—gives colistin its broad gram-negative spectrum but also contributes to its nephrotoxicity and neurotoxicity profiles.

During the 1950s and 1960s, colistin saw clinical use primarily in topical and oral formulations. However, the emergence of safer, broader-spectrum antibiotics (tetracyclines, aminoglycosides, and early beta-lactams) relegated colistin to niche applications. Its parenteral use was limited by documented kidney and nerve toxicity, and it largely disappeared from mainstream clinical practice in developed nations by the 1970s.

Regulatory Hibernation (1970s–1990s)

For nearly three decades, colistin languished outside major drug development pipelines. It remained available in some European markets and was used extensively in veterinary medicine, particularly in livestock feed additives for growth promotion.

During this period, regulatory agencies—including the FDA and EMA—did not actively pursue new indications or formulations. The compound was not forgotten, but it was deemed less relevant as newer agents dominated clinical practice. This regulatory quiet reflected the antibiotic landscape of the era: resistance was manageable, and alternatives were abundant.

The Resistance Crisis & Regulatory Reawakening (1990s–2000s)

By the late 1990s, the epidemiology of gram-negative resistance shifted dramatically. Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and later carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii emerged as major nosocomial threats.

With dwindling options, clinicians and researchers began revisiting colistin. Regulatory agencies recognized that colistin represented a potentially life-saving therapy for infections caused by pan-resistant gram-negative pathogens. The shift was pragmatic: in the face of untreatable infections, the known toxicity of colistin became an acceptable trade-off.

Clinical Trial Acceleration

Between 2000 and 2010, 119 clinical trials involving colistin were registered across multiple phases and indications, studying everything from intravenous formulations to inhalation therapy for cystic fibrosis lung infections and hospital-acquired pneumonia.

Key studies during this era focused on:

Pharmacokinetics and dosing optimisation in critically ill patients
Combination therapy with carbapenems and other agents
Nephrotoxicity risk stratification and monitoring protocols
Inhalation formulations for respiratory tract infections

Modern Regulatory Approvals (2000s–Present)

FDA Approval

Colistimethate sodium (the inactive prodrug form) was FDA-approved for intravenous use in 2009 under the brand name Coly-Mycin M. The approval came via the expedited pathway as a critical need antibiotic for multidrug-resistant gram-negative infections, particularly Pseudomonas aeruginosa and Acinetobacter baumannii.

The FDA label restricts colistin use to serious infections caused by organisms resistant to other antibiotics, emphasising the risk of nephrotoxicity and neurotoxicity as significant adverse effects requiring careful monitoring.

EMA Authorisation

The EMA approved colistin sodium methanesulfonate (the same active moiety as the FDA product) for serious infections caused by multidrug-resistant gram-negative aerobic bacteria in patients with limited or no alternative treatment options. The EMA label similarly emphasises the risk-benefit calculus: use only when conventional antibiotics have failed or are unsuitable.

Health Canada Approval

Colistin (colistimethate sodium) was approved by Health Canada for treatment of serious infections due to susceptible strains of gram-negative bacteria in patients with limited therapeutic alternatives. Consistent with other jurisdictions, the label highlights nephrotoxicity and neurotoxicity as key safety concerns.

Clinical Development in Newer Formulations

While the intravenous formulation was the first to achieve regulatory approval, subsequent development focused on:

Inhaled Colistin

Studies exploring inhaled colistin for lower respiratory tract infections in cystic fibrosis and ventilator-associated pneumonia have shown promise in achieving high lung concentrations with reduced systemic toxicity. Several formulations entered clinical trials, though regulatory approval timelines have varied by jurisdiction.

Combination Therapy

Major clinical research has evaluated colistin in combination with other agents—particularly carbapenems like meropenem and imipenem—to improve outcomes against difficult-to-treat gram-negative pathogens. Synergy data from in vitro studies and clinical cohorts have informed dosing strategies.

Current Regulatory Status & Clinical Role

Today, colistin occupies a well-defined niche in the antibiotic armamentarium:

Indication: Serious infections caused by multidrug-resistant gram-negative bacteria (especially Pseudomonas, Acinetobacter, and ESBL-producing Enterobacteriaceae) when conventional antibiotics have failed.
Route: Intravenous (most common); inhaled formulations under investigation or approved in select jurisdictions.
Regulatory status: FDA-approved, EMA-authorised, Health Canada-approved.
Monitoring: Mandatory renal function and neurological assessment due to documented nephrotoxicity and neurotoxicity risk.

Why the Regulatory Timeline Matters

Colistin's journey reflects a broader lesson in antibiotic development: compounds once deemed too toxic for routine use become invaluable in the context of resistance. Regulatory agencies had to balance historical safety data with emerging clinical need—a calculation that shifted as antibiotic resistance accelerated.

The 70-year timeline also illustrates the importance of maintaining stewardship of older drugs and not entirely abandoning compounds, even when they fall out of favour. Unlike newer antibiotics—which require years of development and billions in investment—colistin was a known entity that could be rapidly re-evaluated and repositioned.

Related Compounds & Mechanisms

Colistin is part of the broader polymyxin class, which includes its closely related cousin polymyxin B. Both share similar mechanisms (gram-negative cell membrane disruption) and toxicity profiles. Tobramycin and other aminoglycosides are sometimes used in combination with colistin for synergy against multidrug-resistant pathogens.

Understanding colistin's regulatory path also requires familiarity with key concepts like antimicrobial stewardship and minimum inhibitory concentration testing, which guide clinicians in appropriate use.

Veterinary Regulatory Context

Colistin also has a significant regulatory history in veterinary medicine. It has been used as a feed additive for growth promotion in livestock across Europe, Asia, and other regions. In 2016, the EMA restricted colistin use in animals to therapeutic purposes only, phasing out growth-promotion applications to curb the emergence of colistin-resistant bacteria in the food chain. This veterinary restriction underscores how regulatory decisions about a single compound cascade across human and animal health domains.

Colistin Regulatory History: From Discovery to Modern Approval